Artículos (Farmacología, Pediatría y Radiología)
URI permanente para esta colecciónhttps://hdl.handle.net/11441/11030
Examinar
Envíos recientes
Artículo Prognostic significance of mutation type and chromosome fragility in Fanconi anemia(Wiley, 2024-11-19) Ramírez, María José; Pujol, Roser; Minguillón, Jordi; Bogliolo, Massimo; Persico, Ilaria; Cavero, Débora; Fernández-Teijeiro, Ana; Surrallés, Jordi; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Gobierno de España; Instituto de Salud Carlos III; European Union (UE); Generalitat de CatalunyaFanconi anemia (FA) is a rare genetic disease characterized by high phenotypic and genotypic heterogeneity, and extreme chromosome fragility. To better understand the natural history of FA, identify genetic risk and prognostic factors, and develop novel therapeutic strategies, the Spanish Registry of Patients with FA collects data on clinical features, chromosome fragility, genetic subtypes, and DNA sequencing with informed consent of participating individuals. In this article, we describe the clinical evolution of 227 patients followed up for up to 30 years, for whom our data indicate a cumulative cancer incidence of 86% by age 50. We found that patients with lower chromosome fragility had a milder malformation spectrum and better outcomes in terms of later-onset hematologic impairment, less severe bone marrow failure, and lower cancer risk. We also found that outcomes were better for patients with mutations leading to mutant FANCA protein expression (genetic hypomorphism) than for patients lacking this protein. Likewise, prognosis was consistently better for patients with biallelic mutations in FANCD2 (mainly hypomorphic mutations) than for patients with biallelic mutations in FANCA and FANCG, with the lack of the mutant protein in patients with biallelic mutations in FANCG contributing to their poorer outcomes. Our results regarding the clinical impact of chromosome fragility and genetic hypomorphism suggest that mutant FA proteins retain residual activity. This finding should encourage the development of novel therapeutic strategies aimed at partially or fully enhancing mutant FA function, thereby preventing or delaying bone marrow failure and cancer in patients with FA.Artículo Safety and efficacy of immunoguided prophylaxis for cytomegalovirus disease in low-risk lung transplant recipients in Spain: a multicentre, open-label, randomised, phase 3, noninferiority trial(Elsevier, 2025-03-26) Páez Vega, Aurora; Vaquero Barrios, José M.; Ruiz Arabi, Elisa; Iturbe Fernández, David; Alonso, Rodrigo; Ussetti Gil, Piedad; Lobo Acosta, María Ángeles; Gutiérrez Gutiérrez, Belén; Torre Cisneros, Julián; Universidad de Sevilla. Departamento de Medicina; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Instituto de Salud Carlos III; Centro de Investigación Biomédica en Red (CIBER); European Union (UE); Gobierno de España; Sociedad Andaluza de Trasplante de Órganos y Tejidos (SATOT)Background: The standard prophylaxis treatment for cytomegalovirus (CMV) disease in CMV-seropositive lung transplant recipients is six months of prophylaxis with valganciclovir followed by six months of pre-emptive therapy. This protocol is associated with adverse events and risk of resistance. We have previously shown that prophylaxis can be suspended in CMV-seropositive kidney transplant recipients receiving thymoglobulin without increasing the risk of CMV disease and reducing the incidence of neutropenia. The objective of the current study is to demonstrate that immunoguided prophylaxis is effective and safe in seropositive lung transplant recipients. Methods: A phase III, multicentre, randomised, open-label, noninferiority clinical trial was conducted in adult lung transplant recipients. Patients were randomised (1:1) to two groups: (1) immunoguided prophylaxis (IP), consisting of 3 months of universal prophylaxis followed by CMV-specific cell-mediated immunity-guided discontinuation, or (2) standard prophylaxis (SP), consisting of 6 months of prophylaxis followed by pre-emptive therapy, both for a total of 12 months. The noninferiority margin was 7%. The primary and secondary efficacy endpoints were CMV disease and asymptomatic CMV replication at month 18. The primary and secondary safety endpoints were incidence of neutropenia (defined as neutrophil count <1500 cells/μL), incidence of rejection and number of days of valganciclovir prophylaxis. This trial was registered in EudraCT (2018-003300-39) and ClinicalTrials.gov (NCT03699254). This trial has been completed. Findings: Patients were recruited between April 2019 and December 2021 in seven Spanish centres. A total of 150 patients were randomised (75 patients per group). Incidence of CMV disease at month 18 did not differ among groups (18·7% [14 patients] vs. 16·0% [12 patients]; risk difference [RD] −0·03 [95% CI −0·15% to 0·06%]; P = 0·620) but occurred earlier in the IP group compared to the SP group. The proportion of patients who developed CMV disease at ≤180 days after transplant was higher in the IP group compared with the SP group (8% [6 patients] vs. 0% [0 patients]; RD −0·08 [95% CI −0·14 to −0·02; P = 0·009]). Asymptomatic CMV replication was reduced in the IP group vs. the SP group (4·0% [3 patients] vs. 16·0% [12 patients]; adjusted RD 0·12 [95% CI 0·03–0·21; P = 0·009]). A total of 30 patients (40%) in the IP group did not require prophylaxis from month 4 to 12. No significant difference was observed in the proportion of patients with neutropenia during months 4 to 7 (14·7% [11 patients] vs. 25·3% [19 patients]; RD 0·11 [95% CI −0·02 to 0·23]; P = 0·090) or rejection (33·3% [25 patients] vs. 30·7% [23 patients]; RD −0·03 [95% CI −0·18 to 0·12; P = 0·690]). The median days of valganciclovir was lower in the IP group than in the SP group (137 [92–266] vs. 198 [173–281]; P < 0.001). Interpretation: Immunoguided prophylaxis was noninferior to the standard of care in preventing CMV disease in lung transplant recipients. It could be considered for implementing in clinical practice in CMV-seropositive lung transplant recipients upon considering the study limitations.Artículo Grave retraso del neurodesarrollo y estatura en niña inmigrante(2024-11-24) García García, Emilio José; Alonso Luengo, Olga; Sobrino Toro, Manuel; Universidad de Sevilla. Departamento de Farmacología, Pediatría y RadiologíaPresentamos una niña recién llegada de Marruecos, país sin acceso a cribado neonatal, que consulta con nueve años en la urgencia hospitalaria por grave retraso global de neurodesarrollo y enanismo. Los padres referían estreñimiento crónico y que consiguió control cefálico y sedestación con cuatro años, bipedestación con siete, con nueve estaba dando sus primeros pasos y aún no hablaba. Presentaba talla 90 cm (percentil < 1, -7,6 desviación estándar (DE), peso 15 kg (pc < 1, -2,55 DE), índice de masa corporal 18,5 kg/m2 (pc 55, +0,15 DE), hipoacusia, mixedema facial, macroglosia, labios prominentes, falta de la cola de las cejas, distensión abdominal, hernia umbilical, hiporreflexia y contractura en flexión de los miembros inferiores (fig. 1). Se diagnosticó de agenesia tiroidea con tiroxina libre < 0,08 ng/dL, tirotropina > 1.000 mU/L, tiroglobulina < 0,04 ng/mL y ausencia de captación en la gammagrafía. Se observó también aumento del LDL-colesterol (185 mg/dL). Con levotiroxina oral el hábito intestinal, contracturas y deambulación mejoraron y el mixedema y la hipercolesterolemia desaparecieron. (extracto)Artículo Síndrome de Ondine. A propósito de un caso(Elsevier, 2023-10) León Carretero, Susana; Román Fernández, Ana; González Barreda, Carmen; Campo Barasoain, Andrea; Granero Asencio, Mercedes; Universidad de Sevilla. Departamento de Farmacología, Pediatría y RadiologíaRecién nacida a término, sin antecedentes prenatales de interés, ni factores de riesgo infeccioso. Presenta parto inducido por enfermedad materna con amniorrexis de 8 h de evolución que da lugar a líquido meconial espeso, finalizando mediante ventosa para abreviar expulsivo. Nace con test Apgar: 8/9/9 y pH cordón 7,34, precisando aspiración de secreciones, y ventilación con presión positiva intermitente en el primer minuto de vida, con evolución favorable, pero necesitando oxígeno suplementario para mantener adecuada saturación, por lo que ingresa en la Unidad Neonatal. (extracto)Artículo Síndrome tricorrinofalángico: un diagnóstico de visu al alcance del pediatra(Elsevier, 2023-12) Cortés Jiménez, María del Carmen; Fernández García, Raquel María; García García, Emilio José; Universidad de Sevilla. Departamento de Farmacología, Pediatría y RadiologíaEl síndrome tricorrinofalángico (TRPS) es una entidad poco frecuente de herencia autosómica dominante, alta penetrancia y expresividad variable, que se debe a una alteración en el gen TRPS1. Clínicamente se caracteriza por alteraciones del pelo (cabello escaso, adelgazamiento lateral de las cejas) y uñas (distrofia ungueal), leve dismorfia facial (punta nasal bulbosa, filtrum largo y plano, labio superior fino y pabellones auriculares prominentes) y anomalías esqueléticas (talla baja, braquidactilia, desviación de las falanges, epífisis de las falanges en forma de cono, displasia de caderas y osteopenia). Se subdivide en dos tipos: TRPS I (OMIM # 190350), que se debe a variantes patogénicas del gen TRPS1; y TRPS II (OMIM # 150230), que se produce por deleción de genes contiguos en el cromosoma 8 (incluyendo TRPS1 y EXT1) y asocia además osteocondromas y discapacidad intelectual. (extracto)Artículo Absceso mamario neonatal(Lúa Ediciones 3.0, 2024-03-12) Domínguez León, Victoria; Estepa Jiménez, María del Mar; Membrillo Contioso, Estela; Coronel Rodríguez, Cristóbal; Universidad de Sevilla. Departamento de Farmacología, Pediatría y RadiologíaPresentamos el caso de una niña de 27 días de vida, sin antecedentes de interés, que acude a su pediatra por edema y hematoma en la mama derecha. La paciente acude al día siguiente a las urgencias hospitalarias por evolución del cuadro hacia un absceso mamario, teniendo que ser ingresada e iniciando tratamiento antibiótico intravenoso. Dada la mala evolución, y a pesar del tratamiento antibiótico, se decide intervención quirúrgica mediante drenaje y lavado de la cavidad. Finalmente, se resuelve el cuadro sin secuelas posteriores.Artículo Clinical and genetic characteristics of a large international cohort of individuals with rare NR5A1/SF-1 variants of sex development(Elsevier, 2024-01-01) Kouri, C.; Sommer, G.; Martínez de Lapiscina, I.; Naamneh Elzenaty, R.; Tack, L. J. W.; Cools, M.; Faisal Ahmed, S.; Flück, C. E.; García García, Emilio José; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Boveri Foundation Zurich; Swiss National Science FoundationBackground: Steroidogenic factor 1 (SF-1/NR5A1) is essential for human sex development. Heterozygous NR5A1/SF-1 variants manifest with a broad range of phenotypes of differences of sex development (DSD), which remain unexplained. Methods: We conducted a retrospective analysis on the so far largest international cohort of individuals with NR5A1/SF-1 variants, identified through the I-DSD registry and a research network. Findings: Among 197 individuals with NR5A1/SF-1 variants, we confirmed diverse phenotypes. Over 70% of 46, XY individuals had a severe DSD phenotype, while 90% of 46, XX individuals had female-typical sex development. Close to 100 different novel and known NR5A1/SF-1 variants were identified, without specific hot spots. Additionally, likely disease-associated variants in other genes were reported in 32 individuals out of 128 tested (25%), particularly in those with severe or opposite sex DSD phenotypes. Interestingly, 48% of these variants were found in known DSD or SF-1 interacting genes, but no frequent gene-clusters were identified. Sex registration at birth varied, with <10% undergoing reassignment. Gonadectomy was performed in 30% and genital surgery in 58%. Associated organ anomalies were observed in 27% of individuals with a DSD, mainly concerning the spleen. Intrafamilial phenotypes also varied considerably. Interpretation: The observed phenotypic variability in individuals and families with NR5A1/SF-1 variants is large and remains unpredictable. It may often not be solely explained by the monogenic pathogenicity of the NR5A1/SF-1 variants but is likely influenced by additional genetic variants and as-yet-unknown factors.Artículo Contrarréplica a la carta del Dr. Ramón Ugarte(Lúa Ediciones 3.0, 2024-06-04) Coronel Rodríguez, Cristóbal; Flores Méndez, Beatriz; Domínguez León, Victoria; Universidad de Sevilla. Departamento de Farmacología, Pediatría y RadiologíaAnte todo, agradecemos al Dr. Ramón Ugarte, experto en el tema, sus aportaciones e interés por nuestro estudio. Los datos indican que el uso de melatonina en los países desarrollados se está disparando en la última década sin control médico ni percepción por la sociedad de estar consumiendo una hormona, al estar comercializada como complemento alimenticio. Coincidimos con el Dr. Ramón Ugarte, en su carta publicada en febrero de 2024 en esta revista, en que a las casas comerciales le interesa que se hable de la melatonina, aunque sea para mal. Pero, como indica el actual coordinador del Grupo de Trabajo de Sueño de la Asociación Española de Pediatría de Atención Primaria (AEPap), el Dr. Ignacio Cruz, los pediatras españoles necesitamos estudios sobre la melatonina, sus dosis, sus indicaciones… Si los pediatras “miran hacia otro lado” y no hablan de melatonina, no por eso va a dejar de utilizarse y la información que no aporta la ciencia la dará cualquier otra fuente con otros intereses menos nobles. La melatonina se usa en España, ¿por qué si no iba a haber 53 presentaciones comerciales de una misma sustancia? La industria farmacéutica trabaja basándose en estudios de mercado, y esa cantidad pasmosa de productos ─con composición similar, al alcance del consumidor─ existe porque investigaciones comerciales habrán indicado que se van a vender y no hay ninguna regulación que lo impida. (extracto)Artículo ECLIM-SEHOP: how to develop a platform to conduct academic trials for childhood cancer(Springer, 2024-04-10) Juan Ribelles, Antonio; Bautista, Francisco; Cañete, Adela; Rubio San Simón, Alba; Alonso Saladrigues, Anna; Hladun, Raquel; Márquez Vega, Catalina; Fernández-Teijeiro, Ana; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; ACAYE, Uno entre cien mil; Asociación Española Contra el Cáncer (AECC); Asociación Pablo Ugarte; Federación Española de Padres de Niños con Cáncer; Fundación Inocente; Fundación MARIntroduction: ECLIM-SEHOP platform was created in 2017. Its main objective is to establish the infrastructure to allow Spanish participation into international academic collaborative clinical trials, observational studies, and registries in pediatric oncology. The aim of this manuscript is to describe the activity conducted by ECLIM-SEHOP since its creation. Methods: The platform’s database was queried to provide an overview of the studies integrally and partially supported by the organization. Data on trial recruitment and set-up/conduct metrics since its creation until November 2023 were extracted. Results: ECLIM-SEHOP has supported 47 studies: 29 clinical trials and 18 observational studies/registries that have recruited a total of 5250 patients. Integral support has been given to 25 studies: 16 trials recruiting 584 patients and nine observational studies/registries recruiting 278 patients. The trials include front-line studies for leukemia, lymphoma, brain and solid extracranial tumors, and other key transversal topics such as off-label use of targeted therapies and survivorship. The mean time from regulatory authority submission to first patient recruited was 12.2 months and from first international site open to first Spanish site open was 31.3 months. Discussion: ECLIM-SEHOP platform has remarkably improved the availability and accessibility of international academic clinical trials and has facilitated the centralization of resources in childhood cancer treatment. Despite the progressive improvement on clinical trial set-up metrics, timings should still be improved. The program has contributed to leveling survival rates in Spain with those of other European countries that presented major differences in the past.Artículo La dieta sin gluten cambia el perfil lipídico de los niños y adolescentes celíacos(Lúa Ediciones 3.0, 2024-10-10) Flores Méndez, Beatriz; Coronel Rodríguez, Cristóbal; Universidad de Sevilla. Departamento de Farmacología, Pediatría y RadiologíaIntroducción: la dieta sin gluten es el único tratamiento de la enfermedad celíaca. Los productos sin gluten contienen un mayor porcentaje de carbohidratos y lípidos saturados, lo que puede producir problemas metabólicos a largo plazo. Dado que la arteriosclerosis es la principal causa de morbimortalidad en los países desarrollados, el objetivo de este trabajo es analizar el perfil lipídico de niños y adolescentes por debajo de los 18 años tras su diagnóstico como celíacos y su modificación después de iniciar el tratamiento. Material y métodos: se llevó a cabo un estudio observacional retrospectivo de niños diagnosticados de enfermedad celíaca sin otra comorbilidad que seguían una dieta sin gluten estricta. Se recogieron y compararon los perfiles lipídicos al debut de la enfermedad, al año y a los 6 años del inicio de la dieta sin gluten. Resultados: en el estudio se incluyó a 24 pacientes pediátricos. Se objetivó un ascenso de los niveles de colesterol total y un descenso de los niveles de triglicéridos, ambos con significación estadística (p <0,05). Conclusiones: creemos importante analizar el perfil nutricional de los pacientes celíacos pediátricos al diagnóstico de la enfermedad, así como en el seguimiento de su dieta sin gluten, para poder detectar problemas metabólicos y/o nutricionales de manera precoz, atajando el desarrollo de consecuencias que pueden dar la cara ya desde el periodo infantil.Artículo Hodgkin lymphoma: hypodense lesions in mediastinal masses(Nature Research, 2024-06-25) Damek, Adrian; Kurch, Lars; Franke, Friedrich Christian; Attarbaschi, Andishe; Beishuizen, Auke; Cepelova, Michaela; Fernández-Teijeiro, Ana; Stoevesandt, Dietrich; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Projekt DEALHypodense volumes (HDV) in mediastinal masses can be visualized in a computed tomography scan in Hodgkin lymphoma. We analyzed staging CT scans of 1178 patients with mediastinal involvement from the EuroNet-PHL-C1 trial and explored correlations of HDV with patient characteristics, mediastinal tumor volume and progression-free survival. HDV occurred in 350 of 1178 patients (29.7%), typically in larger mediastinal volumes. There were different patterns in appearance with single lesions found in 243 patients (69.4%), multiple lesions in 107 patients (30.6%). Well delineated lesions were found in 248 cases (70.1%), diffuse lesions were seen in 102 cases (29.1%). Clinically, B symptoms occurred more often in patients with HDV (47.7% compared to 35.0% without HDV (p = 0.039)) and patients with HDV tended to be in higher risk groups. Inadequate overall early-18F-FDG-PET-response was strongly correlated with the occurrence of hypodense lesions (p < 0.001). Patients with total HDV > 40 ml (n = 80) had a 5 year PFS of 79.6% compared to 89.7% (p = 0.01) in patients with HDV < 40 ml or no HDV. This difference in PFS is not caused by treatment group alone. HDV is a common phenomenon in HL with mediastinal involvement.Artículo Impact of pediatric inflammatory bowel disease on caregivers' work productivity: A multicenter study by the SEGHNP(Wiley, 2024-07-28) Velasco Rodríguez‐Belvís, Marta; Palomino, Laura; Pujol Muncunill, Gemma; Martin Masot, Rafael; Muñoz Codoceo, Rosa Ana; Barrio Torres, Josefa; Navas López, Víctor Manuel; Martín de Carpi, Javier; Millán Jiménez, Antonio; Universidad de Sevilla. Departamento de Farmacología, Pediatría y RadiologíaObjectives/Background: Pediatric inflammatory bowel disease (PIBD) poses significant challenges not only to patients but also to their families, particularly affecting the work productivity of caregivers. This Spanish multicenter study aims to elucidate the extent of this impact. Materials and Methods: A cross-sectional, multicenter study was conducted between February 2021 and June 2023, involving parents or caregivers of PIBD patients aged 10–18 years. The study utilized the Work Productivity and Activity Impairment (WPAI) questionnaires alongside assessing disease activity and socioeconomic status to quantify work productivity loss and its economic implications. Results: The study included 370 patients from 37 centers, highlighting a significant loss of work productivity among caregivers, especially mothers. The global unemployment rate was notably higher in this group compared to national averages (22.9% vs. 13.8%), particularly among females (30.7% vs. 13.7%), with absenteeism and presenteeism rates (26.4% and 39.9%) significantly impacting the caregivers' ability to work. The study also identified active disease and treatment with biologics or steroids as risk factors for increased work productivity loss. Conclusions: Caregivers of children with inflammatory bowel disease face considerable challenges in maintaining employment, with a notable economic impact due to lost work hours. The findings underscore the need for targeted support and interventions to assist these families, suggesting potential areas for policy improvement and support mechanisms to mitigate the socioeconomic burden of PIBD on affected families.Artículo Lenvatinib Plus Ifosfamide and Etoposide in Children and Young Adults with Relapsed Osteosarcoma: A Phase 2 Randomized Clinical Trial(American Medical Association, 2024-10-17) Gaspar, Nathalie; Hung, Giun Yi; Strauss, Sandra J.; Campbell-Hewson, Quentin; Cruz, Filemón S. de la; Glade Bender, Julia L.; Márquez Vega, Catalina; Bautista, Francisco; Universidad de Sevilla. Departamento de Farmacología, Pediatría y RadiologíaImportance : The combination of ifosfamide and etoposide (IE) is commonly used to treat relapsed or refractory osteosarcoma; however, second-line treatment recommendations vary across guidelines. Objective : To evaluate whether the addition of lenvatinib to IE (LEN-IE) improves outcomes in children and young adults with relapsed or refractory osteosarcoma. Design, Setting, and Participants : The OLIE phase II, open-label, randomized clinical trial was conducted globally across Europe, Asia and the Pacific, and North America. From March 22, 2020, through November 11, 2021, the trial enrolled patients aged 2 to 25 years with high-grade osteosarcoma, measurable or evaluable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1), and 1 to 2 prior lines of systemic treatment. The data analyses were performed between March 22, 2020 (first patient in) and June 22, 2022 (data cutoff for the primary analysis), and September 29, 2023 (end of study final database lock). Interventions : The OLIE trial assessed the efficacy and safety of lenvatinib (14 mg/m2 taken orally once daily) combined with up to 5 cycles of ifosfamide (3000 mg/m2 intravenously) and etoposide (100 mg/m2 intravenously) on days 1 to 3 of each cycle vs IE alone at the same doses. Patients randomized to IE could cross over to receive lenvatinib upon disease progression by independent imaging review. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) per RECIST 1.1 by independent imaging review. The Kaplan-Meier method was used to estimate the PFS distribution, with a prespecified 1-sided significance threshold of .025 by stratified log-rank test. Secondary end points included PFS rate at 4 months and overall survival. Adverse events were summarized using descriptive statistics. Results : A total of 81 patients were enrolled (median [IQR] age, 15.0 [12.0-18.0] years; 46 males [56.8%]), with 40 in the LEN-IE arm and 41 in the IE arm. Median PFS was 6.5 months (95% CI, 5.7-8.2 months) for the LEN-IE arm and 5.5 months (95% CI, 2.9-6.5 months) for the IE arm (hazard ratio [HR], 0.54; 95% CI, 0.27-1.08; 1-sided P = .04). The rate of PFS at 4 months was 76.3% (95% CI, 59.3%-86.9%) in the LEN-IE arm and 66.0% (95% CI, 47.7%-79.2%) in the IE arm. Median overall survival was 11.9 months (95% CI, 10.1 months to not estimable) with LEN-IE and 17.4 months (95% CI, 14.2 months to not estimable) with IE (HR, 1.28; 95% CI, 0.60-2.70; 1-sided nominal P = .75). Grade 3 or higher treatment-related adverse events occurred in 35 of 39 patients (89.7%) in the LEN-IE arm and 31 of 39 patients (79.5%) in the IE arm. Conclusions and Relevance : Although LEN-IE did not meet prespecified statistical significance for improved PFS vs IE, this study demonstrates the importance of international collaboration and randomized clinical trials in patients with relapsed or refractory osteosarcoma and may inform future trial design.Artículo Exploring genetic testing requests, genetic alterations and clinical associations in a cohort of children with autism spectrum disorder(Springer, 2024-04-08) Garrido-Torres, Nathalia; Marqués Rodríguez, Renata; Alemany-Navarro, María; Sánchez-García, Javier; García-Cerro, Susana; Ayuso, María Irene; González-Meneses López, Antonio; Martínez-Mir, Amalia; Ruiz Veguilla, Miguel; Crespo Facorro, Benedicto; Universidad de Sevilla. Departamento de Psiquiatría; Universidad de Sevilla. CTS1086: Psiquiatría TraslacionalSeveral studies show great heterogeneity in the type of genetic test requested and in the clinicopathological characteristics of patients with ASD. The following study aims, firstly, to explore the factors that might influence professionals’ deci sions about the appropriateness of requesting genetic testing for their patients with ASD and, secondly, to determine the prevalence of genetic alterations in a representative sample of children with a diagnosis of ASD. Methods: We studied the clinical factors associated with the request for genetic testing in a sample of 440 children with ASD and the clinical factors of present genetic alterations. Even though the main guidelines recommend genetic testing all children with an ASD diagnosis, only 56% of children with an ASD diagnosis were genetically tested. The prevalence of genetic altera tions was 17.5%. These alterations were more often associated with intellectual disability and dysmorphic features. There are no objective data to explicitly justify the request for genetic testing, nor are there objective data to justify requesting one genetic study versus multiple studies. Remarkably, only 28% of males were genetically tested with the recommended tests (fragile X and CMA). Children with dysmorphic features and organic comorbidities were more likely to be genetic tested than those without. Previous diagnosis of ASD (family history of ASD) and attendance at specialist services were also associated with Genetically tested Autism Spectrum Disorder GTASD. Our findings emphasize the importance of establishing algorithms to facilitate targeted genetic consultation for individuals with ASD who are likely to benefit, con sidering clinical phenotypes, efficiency, ethics, and benefits.Artículo Diferenciación entre hiperplasia tímica de rebote y recaída tímica después de quimioterapia en el linfoma de Hodgkin pediátrico(Wiley, 2023-05-27) Franke, Friedrich Christian; Damek, Adrian; Steglich, Jonas; Kurch, Lars; Hasenclever, Dirk; Georgi, Thomas W.; Fernández-Teijeiro, Ana; Stoevesandt, Dietrich; Universidad de Sevilla. Departamento de Farmacología, Pediatría y RadiologíaBackground: Rebound thymic hyperplasia (RTH) is a common phenomenon caused by stress factors such as chemotherapy (CTX) or radiotherapy, with an incidence between 44% and 67.7% in pediatric lymphoma. Misinterpretation of RTH and thymic lymphoma relapse (LR) may lead to unnecessary diagnostic procedures including invasive biopsies or treatment intensification. The aim of this study was to identify parameters that differentiate between RTH and thymic LR in the anterior mediastinum. Methods: After completion of CTX, we analyzed computed tomographies (CTs) and magnetic resonance images (MRIs) of 291 patients with classical Hodgkin lymphoma (CHL) and adequate imaging available from the European Network for Pediatric Hodgkin lymphoma C1 trial. In all patients with biopsy-proven LR, an additional fluorodeoxyglucose (FDG)-positron emission tomography (PET)-CT was assessed. Structure and morphologic configuration in addition to calcifications and presence of multiple masses in the thymic region and signs of extrathymic LR were evaluated. Results: After CTX, a significant volume increase of new or growing masses in the thymic space occurred in 133 of 291 patients. Without biopsy, only 98 patients could be identified as RTH or LR. No single finding related to thymic regrowth allowed differentiation between RTH and LR. However, the vast majority of cases with thymic LR presented with additional increasing tumor masses (33/34). All RTH patients (64/64) presented with isolated thymic growth. Conclusion: Isolated thymic LR is very uncommon. CHL relapse should be suspected when increasing tumor masses are present in distant sites outside of the thymic area. Conversely, if regrowth of lymphoma in other sites can be excluded, isolated thymic mass after CTX likely represents RTH.Artículo Linking antimicrobial resistance surveillance to antibiotic policy in healthcare settings: the COMBACTE-Magnet EPI-Net COACH project(Oxford University Press (OUP), 2020-12-06) Pezzani, Maria Diletta; Mazzaferri, Fulvia; Compri, Monica; Galia, Liliana; Mutters, Nico T.; Kahlmeter, Gunnar; Rodríguez-Baño, Jesús; Neth, Olaf; Universidad de Sevilla. Departamento de Medicina; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Unión EuropeaObjectives: To systematically summarize the evidence on how to collect, analyse and report antimicrobial resistance (AMR) surveillance data to inform antimicrobial stewardship (AMS) teams providing guidance on empirical antibiotic treatment in health care settings. Methods: The research group identified 10 key questions about the link between AMR surveillance and AMS using a checklist of 9 elements for good practice in health research priority settings and a modified 3D combined approach matrix, and conducted a systematic review of published original studies and guidelines on the link between AMR surveillance and AMS. Results: The questions identified focused on AMS team composition; minimum infrastructure requirements for AMR surveillance; organisms, samples and susceptibility patterns to report; data stratification strategies; reporting frequency; resistance thre sholds to drive empirical therapy; surveillance in high-risk hospital units, long-term care, outpatient and veterinary settings; and surveillance data from other countries. Twenty guidelines and sevenoriginal studies on the implementation of AMR surveillance aspart of an AMS programme were included in the literature review. Conclusions: The evidence summarized in this review provides a useful basis for a more integrated process of developing procedures to report AMR surveillance data to drive AMS interventions. These procedures should be extended to settings outside the acute-care institutions, such as long-term care, outpatient and veterinary. Without proper AMR surveillance, implementation of AMS policies cannot contribute effectively to the fight against MDR pathogens and may even worsen the burden of adverse events from such interventions.Artículo Extending the phenotypes associated with TRIO gene variants in a cohort of 25 patients and review of the literature(Wiley, 2023-03-23) Gazdagh, Gabriella; Hunt, David; Cueto González, Anna María; Pons Rodríguez, Monserrat; Chaudhry, Ayeshah; Madruga, Marcos; González-Meneses López, Antonio; Baralle, Diana; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Agence Nationale de la Recherche; National Institute for Health and Care Research; National Institute for Health ResearchThe TRIO gene encodes a rho guanine exchange factor, the function of which is to exchange GDP to GTP, and hence to activate Rho GTPases, and has been described to impact neurodevelopment. Specific genotype-to-phenotype correlations have been established previously describing striking differentiating features seen in variants located in specific domains of the TRIO gene that are associated with opposite effects on RAC1 activity. Currently, 32 cases with a TRIO gene alteration have been published in the medical literature. Here, we report an additional 25, previously unreported individuals who possess heterozygous TRIO variants and we review the literature. In addition, functional studies were performed on the c.4394A > G (N1465S) and c.6244-2A > G TRIO variants to provide evidence for their pathogenicity. Variants reported by the current study include missense variants, truncating nonsense variants, and an intragenic deletion. Clinical features were previously described and included developmental delay, learning difficulties, microcephaly, macrocephaly, seizures, behavioral issues (aggression, stereotypies), skeletal problems including short, tapering fingers and scoliosis, dental problems (overcrowding/delayed eruption), and variable facial features. Here, we report clinical features that have not been described previously, including specific structural brain malformations such as abnormalities of the corpus callosum and ventriculomegaly, additional psychological and dental issues along with a more recognizable facial gestalt linked to the specific domains of the TRIO gene and the effect of the variant upon the function of the encoded protein. This current study further strengthens the genotype-to-phenotype correlation that was previously established and extends the range of phenotypes to include structural brain abnormalities, additional skeletal, dental, and psychiatric issues.Artículo Generation of mesenchymal stromal cells from urine-derived iPSCs of pediatric brain tumor patients(Frontiers Media, 2023-01-26) Baliña Sánchez, Carmen; Aguilera, Yolanda; Adán, Norma; Sierra Párraga, Jesús María; Olmedo Moreno, Laura; Panadero Morón, Concepción; Cabello Laureano, Rosa; Márquez Vega, Catalina; Martín Montalvo, Alejandro; Capilla González, Vivian; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Instituto de Salud Carlos III; Asociación Española Contra el Cáncer (AECC); Junta de Andalucía; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Gobierno de EspañaHuman induced pluripotent stem cells (iPSCs) provide a virtually inexhaustible source of starting material for next generation cell therapies, offering new opportunities for regenerative medicine. Among different cell sources for the generation of iPSCs, urine cells are clinically relevant since these cells can be repeatedly obtained by non-invasive methods from patients of any age and health condition. These attributes encourage patients to participate in preclinical and clinical research. In particular, the use of urine-derived iPSC products is a convenient strategy for children with brain tumors, which are medically fragile patients. Here, we investigate the feasibility of using urine samples as a source of somatic cells to generate iPSC lines from pediatric patients with brain tumors (BT-iPSC). Urinary epithelial cells were isolated and reprogrammed using non-integrative Sendai virus vectors harboring the Yamanaka factors KLF4, OCT3/4, SOX2 and C-MYC. After reprogramming, BT-iPSC lines were subject to quality assessment and were compared to iPSCs obtained from urine samples of non-tumor pediatric patients (nonT-iPSC). We demonstrated that iPSCs can be successfully derived from a small volume of urine obtained from pediatric patients. Importantly, we showed that BT-iPSCs are equivalent to nonT-iPSCs in terms of morphology, pluripotency, and differentiation capacity into the three germ layers. In addition, both BT-iPSCs and nonT-iPSCs efficiently differentiated into functional mesenchymal stem/stromal cells (iMSC) with immunomodulatory properties. Therefore, this study provides an attractive approach to non-invasively generate personalized iMSC products intended for the treatment of children with brain tumors.Artículo Genetic diagnosis of Duchenne and Becker muscular dystrophy through mRNA analysis: new splicing events(Grupo editorial BMJ, 2022-12-19) Segarra Casas, Alba; Domínguez González, Cristina; Hernández Laín, Aurelio; Sánchez Calvin, María Teresa; Camacho, Ana; Rivas, Eloy; Campo Barasoain, Andrea; Gonzalez Quereda, Lidia; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Instituto de Salud Carlos III; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); Gobierno de EspañaBackground: Up to 7% of patients with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) remain genetically undiagnosed after routine genetic testing. These patients are thought to carry deep intronic variants, structural variants or splicing alterations not detected through multiplex ligation-dependent probe amplification or exome sequencing. Methods: RNA was extracted from seven muscle biopsy samples of patients with genetically undiagnosed DMD/BMD after routine genetic diagnosis. RT-PCR of the DMD gene was performed to detect the presence of alternative transcripts. Droplet digital PCR and whole-genome sequencing were also performed in some patients. Results: We identified an alteration in the mRNA level in all the patients. We detected three pseudoexons in DMD caused by deep intronic variants, two of them not previously reported. We also identified a chromosomal rearrangement between Xp21.2 and 8p22. Furthermore, we detected three exon skipping events with unclear pathogenicity. Conclusion: These findings indicate that mRNA analysis of the DMD gene is a valuable tool to reach a precise genetic diagnosis in patients with a clinical and anatomopathological suspicion of dystrophinopathy that remain genetically undiagnosed after routine genetic testing.Artículo Optimising urinary catecholamine metabolite diagnostics for neuroblastoma(Wiley, 2023-04-03) Matser, Yvette A.H.; Verly, Iedan R.N.; van der Ham, Maria; de Sain-van der Velden, Monique G.M.; Verhoeven-Duif, Nanda M.; Ash, Shifra; Cangemi, Giuliana; Barco, Sebastiano; Popovic, Maja Beck; van Kuilenburg, André B.P.; Tytgat, Godelieve A.M.; Márquez Vega, Catalina; Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología; Villa Joep FoundationIntroduction: The analysis of urinary catecholamine metabolites is a cornerstone of neuroblastoma diagnostics. Currently, there is no consensus regarding the sampling method, and variable combinations of catecholamine metabolites are being used. We investigated if spot urine samples can be reliably used for analysis of a panel of catecholamine metabolites for the diagnosis of neuroblastoma. Methods: Twenty-four-hour urine or spot urine samples were collected from patients with and without neuroblastoma at diagnosis. Homovanillic acid (HVA), vanillylmandelic acid (VMA), dopamine, 3-methoxytyramine, norepinephrine, normetanephrine, epinephrine and metanephrine were measured by high-performance liquid chromatography coupled with fluorescence detection (HPLC-FD) and/or ultra-performance liquid chromatography coupled with electrospray tandem mass spectrometry (UPLC-MS/MS). Results: Catecholamine metabolite levels were measured in urine samples of 400 neuroblastoma patients (24-hour urine, n = 234; spot urine, n = 166) and 571 controls (all spot urine). Excretion levels of catecholamine metabolites and the diagnostic sensitivity for each metabolite were similar in 24-hour urine and spot urine samples (p > .08 and >.27 for all metabolites). The area under the receiver-operating-characteristic curve (AUC) of the panel containing all eight catecholamine metabolites was significantly higher compared to that of only HVA and VMA (AUC = 0.952 vs. 0.920, p = .02). No differences were observed in metabolite levels between the two analysis methods. Conclusion: Catecholamine metabolites in spot urine and 24-hour urine resulted in similar diagnostic sensitivities. The Catecholamine Working Group recommends the implementation of spot urine as standard of care. The panel of eight catecholamine metabolites has superior diagnostic accuracy over VMA and HVA.